Isothiocyanopyridine derivatives

ABSTRACT

New isothiocyanopyridines of the formula   WHEREIN R1 represents hydrogen, alkyl, substituted alkyl, cycloalkyl, Cycloalkenyl, or a group of the formula   WHEREIN R3, R4 and R5 stand for hydrogen, alkyl, phenyl, benzyl, dialkylamino, alkoxycarbonyl, mono- or dialkylcarbamoyl, alkanoyl, halogen, nitro, alkoxy, alkylthio, halogenalkyl, cyano, hydroxy, aryloxy, arylthio, arylamino, aralkoxy, aralkylthio or aralkylamino, Q REPRESENTS 0 TO 6, X represents oxygen, sulphur, sulphonyl or the group   wherein R6 stands for hydrogen, alkyl, alkenyl, dialkylaminoalkyl, alkoxycarbonyl, alkanoyl, or together with the nitrogen atom and the substituent R1 it represents a saturated or unsaturated heterocycle, which can further contain oxygen, sulphur, nitrogen or the group N-R7, wherein R7 represents hydrogen, methyl or ethyl, R2 represents hydrogen or halogen, and in each case one of the symbols m and n denotes 1 while the other is 0, AND THEIR ACID ADDITION SALTS AND QUATERNARY SALTS NON TOXIC TO WARM-BLOODED ANIMALS.

United States Patent [1 1 Schmid et al.

[ Dec. 30, 1975 ISOTHIOCYANOPYRIDINE DERIVATIVES [75] Inventors: Wolfgang Schmid, Therwil; Ernst Gutzwiller, Rheinfelden; Urs Meyer,

Riehen, all of Switzerland [73] Assignee: Ciba-Geigy Corporation, Ardsley,

[22] Filed: Aug. 8, 1973 21 Appl. No.: 386,796

[30] Foreign Application Priority Data Aug. 10, 1972 Switzerland 11886/72 Aug. 10, 1972 Switzerland ll887/72 [52] US. Cl... 260/294.8 E; 260/247.l; 260/293.69; 260/294.8 G; 424/263 Int. Cl. C07D 213/74 Field of Search 260/294.8 E, 294.8 G

[56] References Cited UNITED STATES PATENTS 9/1974 Dickinson et al. 260/294.8 E

OTHER PUBLICATIONS Roberts et al., Basic Principles of Organic Chemistry, Benjamin Publishers, p. 806, (1965).

Primary Examiner-Alan L. Rotman Attorney, Agent, or Firml-larry Falber; Frederick H. Rabin [57] ABSTRACT New isothiocyanopyridines of the formula (NOS) wherein R represents hydrogen, alkyl, substituted alkyl, cycloalkyl, Cycloalkenyl, or a group of the formula 5 (NCS) wherein R R and R stand for hydrogen, alkyl, phenyl, benzyl, dialkylamino, alkoxycarbonyl, monoor dialkylcarbamoyl, alkanoyl, halogen, nitro, alkoxy, alkylthio, halogenalkyl, cyano, hydroxy, aryloxy, arylthio, arylamino, aralkoxy, aralkylthio or aralkylamino,

q represents 0 to 6,

X represents oxygen, sulphur, sulphonyl or the group 4 Claims, No Drawings ISOTHIOCYANOPYRIDINE DERIVATIVES The present invention relates to isothiocyanopyridines, to processes for the preparation of these new compounds, to anthelmintic agents, as well as to agents for defoliation and desiccation which contain these compounds, as active substance.

Among the endoparasites occurring in warm-blooded animals, the helminths in particulardo great harm. For example, animals infested with worms suffer not only inhibited growth but also, in some cases, such severe injury that the animals die. It is therefore of great importance that agents be developed which are suitable for the control of helminthsand of their development stages, as well as for the prevention of infestation by these parasites. The term helminths in the present description covers nematodes, cestodes and trematodes, that is, worms of the gastronintestinal tract, of the liver and of other organs. A number of substances having an anthelmintic action have become known, but these are frequently not able to fully satisfy requirements: they may be insufficiently effective in compatible doses, or produce in therapeutically effective doses undesirable side effects, or have much too narrow a range of action. Thus, for example, racemic 2,3,5,6-tetrahydro-6'phenyl-imidazo(2,l-5 )thiazole, known from the Dutch Pat. Specification No. 6,505,806, is effective only against nematodes, but not against trematodes and cestodes.

The new isothiocyanopyridines correspond to formula 1 wherein 1 R represents hydrogen, a straight-chain or branched alkyl or' alkenyl radical having 1 to 17 carbon atoms, which can be substituted by halogen, hydroxyl, lower alkoxy, phenoxy, lower alkylthio, lower alkylamino, di-lower alkylamino, cycloalkyl having 3 to 6 carbon atoms, alkanoyl having 1 to 6 carbon atoms, or by a benzoyl radical optionally substituted by lower alkyl, halogen, trifluoromethyl or nitro, a mono-, biortricyclic cycloalkyl or cycloalkenyl radical having 3 to 10 carbon atoms in the ring structure, optionally monoor disubstituted by lower alkyl, whereby biand tricyclic radicals can be bound also by way of a methylene group to the group X, or a radical of the formula wherein R R and R stand for hydrogen, straight-chain or branched alkyl having at most 5 carbon atoms, phenyl, benzyl, dialkylamino having a maximum of 4 carbon atoms, alkoxycarbonyl, monoor dialkylcarbamoyl having 2-6 carbon atoms, alkanoyl having 2-5 carbon atoms, halogen, nitro, alkoxy or alkylthiohaving at most 4 carbon atoms, haloalkyl, cyano, hydroxy, optionally substituted aryloxy, arylthio or arylamino, or optionally substituted aralkoxy, aralkylthio or aralkylamino having at most 3 carbon atoms in the alkyl chain,

q represents 0 to 6,

X represents oxygen, sulphur, sulphonyl (SO or the group wherein R stands for hydrogen, an alkyl or alkenyl radical having 1 to 15 carbon atoms, a dimethylamino or diethylamino-lower-alkyl radical, a lower alkoxycarbonyl radical, a lower-alkanoyl radical, or together with the nitrogen atom and the substituent R it represents a saturated or unsaturated heterocycle having 4 to 6 carbon atoms, which can further contain oxygen, sulphur, nitrogen or the group N-R wherein R represents hydrogen, methyl or ethyl,

R represents hydrogen or halogen, and in each case one of the symbols m and n denotes 1 while the other is O,

and include the acid addition salts and quaternary salts non-toxic to warm-blooded animals.

The following may be mentioned as examples of straight-chain or branched alkyl radicals having up to 17 carbon atoms: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl, n-amyl, isoamyl, hexyl, l-ethylpentyl, octyl, undecyl, dodecyl, pentadecyl or heptadecyl.

Examples of straight-chain or branched alkenyl radicals are n-propenyl, a-methylvinyl, 9-decenyl or 8-heptadecenyl. The term lower alkyl denotes a straightchain or branched alkyl radical having 1 to 6, preferably 1 to 4, carbon atoms.

The meaning of cycloalkyl or cycloalkenyl radicals includes also ring structures which can be substituted by methyl, ethyl, n-propyl or isopropyl. Given as examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 3,4-dimethylcyclobutyl, 2,3-dimethylcyclopropyl, 4-methylcyclohexyl, 4-isopropylcyclohexyl, 3,S-bis-(ethyl)cyclohexyl, norbornyl, norbornylmethyl and adamantyl.

The term halogen embraces fluorine, chlorine and bromine.

Saturated or unsaturated heterocycles formed from the substituents R and R together with the N-atom bound to them are, for example, pyrrolidine, piperidine, Z-methylpiperidine, 4-methylpiperidine, piperazine, N'-methyland N'-ethylpiperazine, morpholine, isomorpholine, thiomorpholine, hexamethyleneimine, pyrrole, indole, imidazole, imidazoline, pyrazole and pyrazoline.

The portion of the substituents on the pyridine ring is to be so arranged that the substituent bound by way of the bridge-member X takes the position 2 or 4, and the NCS-group the position 3 or 5.

Suitablesalts ofthe isothiocyanopyridines, non-toxic to warm-blooded animals, are addition compounds with inorganic or organic acids, preferably relatively strong acids,- e.g.; hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, adipic acid, maleic acid, tartaric acid, lactic acid, citric acid, glutamic acid, aconitic acid, sulphamic acid, methanesulphonic acid and p-toluenesulphonic'acid. Where the basicity of the substituents on the pyridine ring permit it, salts may also be formed with weaker, preferably organic acids.

It is also possible to use quaternary salts obtained on the pyridine ring or on the substituent by reaction with alkylating agents such as, e.g., alkyl halides or sulphuric acid alkyl esters.

The compounds of formula I are highly effective against helminths, and can also be employed for defoliation and desiccation of unlignified parts of plants above the soil. The active substances are particularly suitable for defoliation and desiccation of cotton plants, leguminosae, sorghum,- soya beans, potatoes and grape vines before the harvest, without impairment of subsequent ripening. Furthermore, these active substances" may be used also for the treatment of plants such as ornamental plants (chrysanthemums, roses) or tree-nursery-material (ornamental shrubs and trees) which are to be transported, as well as for the treatment of plant material intended for seed production.

To be especially emphasised are the compounds of formula I wherein the isothiocyano group is in the 3- or -position, R represents a straight-chain or branched alkyl radical having l to carbon atoms, the cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or the cyclohexyl radical, R represents hydrogen, and R hydrogen, a straight-chain or branched alkyl or alkenyl radical having 1 to 10 carbon atoms, or together with the nitrogen atom and R it represents a saturated or unsaturated heterocycle having 4 to 6 carbon atoms, which can contain, as a further hetero atom, also oxygen sulphur or nitrogen or the group wherein R stands for methyl or ethyl.

By virtue of their good biological activity, particularly important sub-groups of the active substances according to the invention are as follows:

pyridine derivatives of the general formula I wherein the NCS-group forms a substituent of the pyridine ring, especially such derivatives in which the NCS-group occupies position 5 of the pyridine ring; pyridine derivatives wherein the NCS-group occupies position 5, the substituent bound by way of X position 2;

pyridine derivatives wherein the NCS-group is in position 5, and the substituent bound by way of X in position 2, and in which one of the radicals R to R, occupies position 4;

pyridine derivatives wherein the NCS-group forms a substituent of the pyridine ring, and the radical X-R denotes an aralkylthio group;

pyridine derivatives wherein the NCS-group forms a substituent of the pyridine ring, and the radical --X--R denotes an aralkyloxy group;

pyridine derivatives wherein the NCS-group forms a substituent of the pyridine ring, and the radical -X-R denotes an aralkylamino group.

The following compounds. have proved to have a 5 particularly high anthelmintic activity:

Z-methylmercapto-S -isothiocyanopyridine 2-ethylmercapto -5 -isothiocyanopyridine, 2-n-propylmercapto-5 -isothiocyanopyridine, 2-iso-propylmercapto-5isothiocyan opyridine, 2-n-butylmercapto-5 isothiocyanopyridine 2-sec.butylmercapto-5 -isothiocyanopyridine 2-n-pentylmercapto-5 -isothiocyanopyridine 2-( l ',1 '-dimethylpropylmercapto)-5-isothio'cyanopyridine, 2-( 3 ,3 "-dimethylpropylmerc apto )-5 -isothiocyano'pyridine 2-n-hexylmercapto-5 -isothiocyanopyridine 2-cyclohexylmercapto-5 -isothiocyanopyridine, 2-( l-ethyl-butylr'nercapto )-5 -isothiocyanopyridine '2-tert.hexylmercapto-5 -isothiocyanopyridine, 2-n-heptylmercapto-5 -isothi'ocyanopyridine Z-tert.heptylmercapto- S-isothiocyanopyridine,

2-n-octylmercapto-5-isothiocyanopyridine 2-n-decylmercapto-5 -isothiocyanopyridine Z-me'thoxy-S -isothioc yanopyridine 2-ethoxy-5 -isothiocyanopyridine,

2-iso-propoxy-5-isothiocyanopyridine,

2-n-butoxy -5 -isothiocyanopyridine '2-n-heptyloxy-5-isothiocyanopyridine,

.2-benzylthio-5-isothiocyanopyridine,

2-benzylthio-3-isothiocyanopyridine, 2-(4-methylbenzylthio)-5-isothiocyanopyridine, 2-(4'-methoxybenzylthio)-5-isothiocyanopyridine, 2-(4'-fluorobenzylthio)-5-isothiocyanopyridine, 2,-(4'-chlorobenzylthio)-5-isothiocyanopyridine, 2-(2'-chlorobenzylthio )-5-isothiocyanopyridine, 2-( 2',4'-dichlorobenzylthio)-5-isothiocyanopyridine, 2-(4'-bromobenzylthio)-5-isothiocyanopyridine, 2-(2'-phenylethylthio 5-isothiocyanopyridine, 2-( 3 -phenylpropylthio )-5 -isothiocyanopyridine 2-(6'-phenyl-hexylthio )-5-isothiocyanopyridine, 2-(4'-methylphenylsulphonyl)-5-isothiocyanopyridine, 2-(4-tert.butylphenylsulphonyl)-5-isothiocyanopyridine, 2-(4'-chlorophenylsulphonyl )-5-isothiocyanopyridine,

2-( 2 ,4 '-dichlorobenzylsulphonyl )-5 -isothiocyanopyridine,

Z-phenoxy-S-isothiocyanopyridine,

2-(4'-methyl-phenoxy)-5-isothiocyanopyridine,

2-( 3 '-methyl-phenoxy )-5-isothiocyanopyridine,

2-(2'-methyl-phenoxy)-5-isothiocyanopyridine,

2-(4'-ethyl-plienoxy)-5-isothiocyanopyridine, 2-(4'-fluorophenoxy)-5-isothiocyanopyridine,

2-( 3 -chlorophenoxy)-5 -isothiocyanopyridine,

2-(2',4'-dichlorophenoxy-5-isothiocyanopryidine,

2-( 3 '-trifluoromethyl-phenoxy -3 -isothiocyanopyridine, 2-(4-methoxy-phenoxy)-5 isothiocyanopyridine, 2-(4'-methoxy-phenoxy)-3-isothiocyanopyridine,

2-( 3 -methoxy-phenoxy )5 -isothiocyanopyridine,

2-(4-fluoroanilino)-5-isothiocyanopyridine,

2-(4'-chloroanilino)-5-isothiocyanopyridine, 2-(4'-bromoanilino)-5-isothiocyanopyridine,

2-(4'-methylanilino)-5-isothiocyanopyridine, I

2-(4'-phenoxyanilino )-5-isothiocyanopyridine,

2-(4'-phenylanilino)-5-isothiocyanopyridine, 2-(4'-methoxyanilino)-5-isothiocyanopyridine, 2-(4'-ethoxyanilino )-5-isothiocyanopyridine.

The following are particularly highly effective as defoliating and desiccating agents:

2-n-butoxy-5-isothiocyanopyridine,

2-n-heptoxy-5-isothiocyanopyridine,

Z-n-heptylthio-S-isothiocyanoparidine,

2-allylthio-5-isothiocyanopyridine,

2-butylthio-5-isothiocyanopyridine, 2-pentylthio-5-isothiocyanopyridine, 2-octylthio-5-isothiocyanopyridine, 2(2-phenylethylthio)-5-isothiocyanopyridine.

The new active substances of formula 1 according to the invention have a wide range of action and are suitable for the control of parasitic nematodes of the orders:

Dracunculoidea,

Ascaroidea (e.g. Ascaridia galli),

Trichinelloidea,

Strongyloidea,

Trichostrongyloidea,

Metastrongyloidea, as well as for the control of cestodes of the families:

Dilepididae (e.g., Hymenolepis nana),

Taeniidae,

Diphyllobotridae, and for the control of trematodes of the families:

Dicrocoelidae,

Fasciolidae (e.g., Fasciola hepatica) Schistosamatidae (e.g., Schistosoma bovis) in the case of domestic and farm animals, such as cattle, sheep, goats, horses, pigs, cats, dogs and poultry. The new active substances can be administered in single doses to the animals, or in repeated doses, the single doses preferably being, depending on the species of the animal, between 25 and 1000 mg per kilogram of body weight. A better effect can be obtained in some cases by a protracted administration'of the active substances, or smaller complete doses may suffice. The active substances or mixtures containing them can also be added to the feed or introduced into drinking troughs. The finished feed contains the substances of formula I preferably in a concentration of ca. 0.05 to L0 per cent by weight.

The new active substances can be administered to the animals perorally or via the abomasum, e.g., in the form of solutions, emulsions, suspensions (drenches),

powders, tablets, boluses and capsules; These preparations are prepared, for example, by use of the'usual solid carriers, such as kaolin, talcum, bentonite, sodium chloride, calcium phosphate, carbohydrates, cellulose powder, cottonseed meal, carbowaxes and gelatine, or liquids such as water, optionally with the addition of surface-active substances such as ionic or nonionic dispersing agents, as well as oils, and other solvents and diluents harmless to the animal organism. If the anthelmintic agents are in the form of feed concentrates, then the carriers used are, for example, production feed, fodder grain or protein concentrates. Such feed concentrates or agents can contain, in addition to the active substances, also additives, vitamins, antibiotics, chemotherapeutical agents, or other pesticides, mainly bacteriostatics, fungistatics, coccidio'statics, also-hormone preparations, substances having anabolic activity, or other substances promoting growth, affecting the quality of the meat of slaughter cattle, or being in some other way beneficial for the organism.

The following known anthelmintics, for example, can be used in combination with the described preparations:

PRINCIPALLY AS NEMATOCIDES Absonal Alcopar Anthelcide Ascaridole Badminth II- Bephenium Bradosol Cambendazol Chlorophos Chlorthion Coumaphos Cyanin Destomycin Diethylcarbamazine Dichlorophene, DDVP l ,4-di-( D-glucosyl)-piperazine Dithiazonine Dow ET/ Dowco 132 Dymanthine l-lCl Egressin Gainex Hexachlorophene Hexylresorcinol lonit Levamisol Mepacrine Methylene violet l-Meth yll -tridecylpiperazinium-4-carboxylic ethyl ester Methyridine Monopar Narlene Neguvon Nematodin Nemural Mebendazol Nidanthel Parbendazol Parvex Phenothiazine Piperazine acid 7 Polymethylene-piperazine Promethazine Pyrantel Pyrathiazine Pyryinium-embonate Rametin Ronnel Santonin Shell 1 808 Stilbazium Tetramisole Thenium Thiabendazole Thymolan Triclofenol Treclofenol-piperazine Vermella PRINC IPALLY AS TREMATOCIDES Acedist Bilevon M Bilevon R Bithionol Disophenol Freon 112 Hetol Hetolin Hexachloroethane l-lexachlorophene l-lilomid Niclofolan Nitroxynil Ranide Tremerad Tribromsalan (Tremasept lI) Zanil Brotianid PRINCIPALLY AS CESTOClDES Eludon Piperazine-hexahydrate Copper sulphate Sodium metaarsenite Eouizol A Thiabendazole Piperazine phosphate Nilzan Tetramisole Zanil Phenothiazine Anthelmintic agents according to the invention, as well as agents for defoliation and desiccation, are produced in a manner known per se by the intimate mixing and grinding of active substances of the general formula I with suitable carriers, optionally with the addition of dispersing agents or solvents which are inert to the active substances. The active substances can be obtained and used in the following forms:

solid preparations: dusts, scattering agents, granulates, (coated granulates, impregnated granulates and homogeneous granulates);

water-dispersible concentrates of active substance:

dispersible powders (wettable powders), pastes and emulsions;

liquid preparations: solutions.

The solid preparations (dusts, scattering agents or granulates) are produced by the mixing of the active substances with solid carriers. Suitable carriers are, for example, the above mentioned carriers, as well as bole, loess, chalk, limestone, ground limestone, dolomite, diatomaceous earth, precipitated silicic acid, alkalineearth silicates, sodium and potassium aluminium silicates (feldspars and mica), calcium and magnesium sulphates, ground synthetic materials, ground vegetable products such as bran, bark dust, sawdust, ground nutshells, residues of plant extractions, active charcoal, etc., singly or as mixtures with each other.

For dusts the particle size of the carriers is advantageously up to ca. 0.1 mm; for scattering agents from ca. 0.075 mm to 0.2 mm; and for granulates 0.2 mm or coarser.

The concentration of active substance in the solid preparations is from 0.5 to

To these mixtures may also be added additives stabilising the active substance, and/or nonionic, anionactive and cation-active substances, which, for example, improve the adhesiveness of the active substances (adhesives and agglutinants), and/or ensure a better wettability (wetting agents) and dispersibility (dispersing agents). Suitable adhesives are, for example, the following: olein/lime mixture, cellulose derivatives (methyl cellulose), hydroxyethylene glycol ethers of monoalkyl and dialkyl phenols having 1 to 15 ethylene oxide radicals per molecule and 8 to 9 carbon atoms in the alkyl radical, ligninsulphonic acids, their alkali metal and alkaline-earth metal salts, polyethylene glycol ethers (carbowaxes), fatty alcohol polyethylene glycol ethers having 5 to 20 ethylene oxide radicals per molecule and 8 to 18 carbon atoms in the fatty alcohol moiety, condensation products of ethylene oxide, prop.- ylene oxide, polyvinyl pyrrolidones, polyvinyl alcohols, condensation products of urea and formaldehyde, as well as latex products.

Water-dispersible concentrates of active substance, i.e., wettable powders, pastes and emulsion concentrates, are agents which can be diluted with water to obtain any desired concentration. They consist of active substance, carrier, optionally additives which sta- 9 bilise the active substance, surface-active substances, and anti-foaming agents and, optionally, solvents. The concentration of active substance in these agents is to 80%.

The wettable powders and pastes are obtained by the mixing and grinding of the active substances with dispersing agents and pulverulent carriers, in suitable devices, until homogeneity is attained. Suitable carriers are, e.g. those previously mentioned in the case of solid preparations. lt is advantageous in some cases to use mixtures of different carriers. Dispersing agents can be, e.g.: condensation products of sulphonated naphthalene and sulphonated naphthalene derivatives with formaldehyde, condensation products of naphthalene or of naphthalenesulpnonic acids with phenol and formaldehyde, as well as alkali, ammonium and alkaline-earth metal salts of ligninsulphonic acid, also alkylarylsulphonates, alkali metal salts and alkaline-earth metal salts of dibutyl naphthalenesulphonic acid, fatty alcohol sulphates, such as salts of sulphated hexadecanols, heptadecanols, octadecanols, and salts of sulphated fatty alcohol glycol ether, the sodium salt of oleyl ethionate, the sodium salt of oleyl methyl tauride, ditertiary acetylene glycols, dialkyl dilauryl ammonium chloride, and fatty acid alkali-metal and alkaline-earth metal salts.

Suitable anti-foaming agents are, for example, silicones.

The active substances are so mixed, ground, sieved and strained with the above mentioned additives that the solid constituent in the case of wettable powders has a particle size not exceeding 0.02 to 0.04 mm, and in the case of pastes not exceeding 0.03 mm. Dispersing agents such as those mentioned in the preceding paragraphs, organic solvents and water are used in the preparation of emulsion concentrates and pastes. The solvents must be practically odourless, non-phytotoxic and inert to the active substances.

Furthermore, the agents according to the invention can be administered to the animals, orally or parenterally, in the formof solutions. For this purpose, the active substance (or several'active substances) of the general formula I is (or are) dissolved or emulsified in suitable organic solvents, solvent mixtures or water. Suitable organic solvents are solvents which are nontoxic and inert to the active substances. The solutions are to contain the active substance in a concentration of from 1 to lsothiocyanopyridines of formula I can be produced according to the invention by a process in which the basic aminopyridines of formula ll R1 (II) wherein R5, R R and q have the meanings given above, and in each case one of the symbols m and n denotes 1 while the other is O, are

a. reacted with a thiocarbonic acid derivative of the formula wherein Hal represents chlorine or bromine, and Y chlorine, bromine or a dialkylamino group; or

b. reacted with a sulphide of the formula fl Alk iii Alk

wherein Alk denotes a lower alkyl radical having at most 4 carbon atoms; or

c. reacted with pentathio-dipercarbonic acid-bis- (trihaloalkyl)-esters; or

d. reacted with phosgene and phosphorus pentasulphide in a solvent or diluent inert to the reactants; or e. converted with benzoylisothiocyanate into the corresponding thiourea, and this thermally decomposed in the presence of a solvent inert to the reactants, preferably in an aromatic hydrocarbon or halogenated hydrocarbon, or in the presence of acids or acid anhydrides; or f. converted with carbon disulphide in the presence of an inorganic base, or of an amine, into the corresponding dithiocarbamic acid salts, and these then dehydrosulphated; or g. reacted with carbon disulphide in the presence of carbodiimides and of a tertiary amine; or h. reacted with ammonium rhodanide in the presence of gaseous hydrogen chloride. The processes are performed in solvents or diluents which are inert to the reactants.

The following, for example, can be used in the process according to the invention: aliphatic and aromatic 1 l hydrocarbons, aliphatic and aromatic-halogenated hydrocarbons, ethers and ethereal compoundssuch as dioxane or tetrahydrofuran, ketones, amides such as dimethylformamide, etc., water, or mixturesof such solvents with water.

1n the preparation of isothiocyano compounds of formula I by the methods given under a) h), temperatures of between 20 and +100C are maintained, preferably of between -10 and +30C, and with application of a dialkylthiocarbamoyl halide such as diethylthiocarbamoyl chloride, or in the case of thermal decomposition according to method e), higher temperatures of between 40 and 200C are used.

The formation of the isothiocyano group involves known methods: reactions of amines with thiophosgene (a) are described in Houben-Weyl, 4th edition, Vol.9, p. 876 (1955), the use of acid-binding agents by O. E. Schultz in Arch. Pharm. 295, 146-151 (1962); the reaction of amines with N,N-diethylthiocarbamoyl chloride (a) has been described in Journal org. Chem. 30,2465 (1965 that with bis-thiocarbamoyl sulphides (b) by F. H. Marquardt in Helv. chim. Acta 49, 1716 (1966), and that with pentathiodipercarbonicacid-bis- (trihalogenoalkyl)-ester (c) by R. Gottfried in Angew. Chem. 78, 985 (1966), and that with phosgene and phosphorus pentasulphide according to Houben-Weyl, 4th edition, Vol. 9, p. 867 ff.

The preferred solvents for the reactions given under (1) and e) are o-dichlorobenzene and chlorobenzene; other, dichlorobenzenes, toluene, xylenes, cumol, etc. are however-also suitable. The thermaldecomposition of thioureas e) is performed in the manner described by J. N. Baxter et. al. in J. Chem. Soc. (1956), p. 659 ff.. The thioureas are produced according to Org. Syntheses I11, 735, (1955). The inorganic bases used in the production of dithiocarbamic acid salts (f) are, e.g., the hydroxides, oxides and carbonates of alkali and alkaline-earth metals, as well as ammonium hydroxide; and the amines used are, e.g. trialkylamines, pyridine bases or ammonia (cp. C.A. 70,3389 q (1969), etc.. Dehydrosulphuration can be carried out oxidatively with metal salts (Brit. Pat. No. 793, 802, Dutch Pat. No. 81,326), e.g. with lead, copper, zinc or iron-Ill salts, iodine, alkali metal hypochlorites and chlorites, preferably with those of potassium and sodium (French Pat. No. 1,311,855), also with suitable acid halides such as phosgene and phosphorus oxychloride (D. Martin et. a1. Chem. Ber. 98, 2425-2426 (1965)), as well as with elementary chlorine and ammonium sulphide (DAS1,192,139) or chloramine T (British Patent No. 1,024,913).

lsothiocyanopyridines of formula 1 are obtainable, for example, by reaction of aminopyridines with thiophosgene in suitable organic solvents, water and mineral acids, preferably in dilute hydrochloric acid, according to:

12 reaction with thiophosgene in organic solvents, water or dilute mineral acid, the effective salts are firstly obtained.

Salts of isothiocyanopyridines of formula 1 can be prepared with strong acids. Salts with weak or diluted acids are producible if one or both substituents R and R carries or carry a basic group, or if X is -N-R The hydrochlorides of this last-mentioned sub-group can also be obtained direct, starting with amino compounds of formula II, if1thiophosgene is used for the reaction in 7 organic solvents, water or dilute hydrochloric acid.

Aminopyridines of formula 11 and their immediate precursors, the nitropyridines, are in some cases known or can be produced by known methods.

[cp. Gifu Yakka Daigaku 13, 34-37 (1963); Rocz.Chem. 42, 795-801 (1968);

Yakugaku Zasshi 78, 1447-1448 (1958),

J'.Chem. Soc. 1948 (1939-1945);

J.Pharm.Soc. Japan 62, -143 (1942); J.Pharm.Soc. Japan 64, N. 7A, 10-11 (1944); J.Pharm.Soc. Japan 72, 1017-1020, (1952);

Brit. Pat. 870027 I Chem. Listy, 49, 731-736;

Collection Czechoslov. Chem. Communs. 20, 1221-6 J. Pharm.Soc. Japan 71, 786-789 (1951);

J. Pharm.Soc. Japan 72, 1141-1144 (1952);

J. Sci. 1nd. R 5 (India) 21 B, 483-486 (1962); S'eifen-oele Fette-wachse 91 (12), 593-595 (1965); Ricerca sci. 8 1, 427-429 (1937);

Gazz. chim. ital. 69, 86-96 (1939).

EXAMPLE 1 Preparation of 2-methylmercapto-5 -isothiocyano-pyridine (Compound 1 EXAMPLE 2 Preparation of Z-ethylsulphonyl-Sisothiocyano-pyridine (Compound 25) 30.8 g of crude 2-ethylsulphonyl-5amino-pyridine, obtained bv catalytic hydrogenation, is dissolved in 250 SCN ml of dioxane. This solution is added dropwise during 15 minutes at room temperature to a mixture of 23 g of thiophosgene and 300 ml of dioxane. The solution is stirred overnight and then stirred into 1.5 liters of ice water. The crystalline precipitate is'chromatographed with methylene chloride through silica gel to obtain the pure final product, M.P. 108 111C.

24.8 g of crude 2-methoxy-5-amino-pyridine, ob- 5 tained by catalytical hydrogenation, is'dissolved in 200 ml of dioxane. This solutionis added at room temperature to a mixture of 25 g of thiophosgene and 200 ml of dioxane, whereby a slight exothermic reaction is ob- 1 14 of 5% Pt-C. Raney nickel and platinum arefiltered off undensuction. and ethanol completely removed from the filtrate. The formed 2-n-h exylamino-5-aminopyridine is sufficiently pure for the next step.

c. 60 g of 2-n-hexylamino-5-aminopyridine in 300 ml of distilled anhydrous dioxane is added dropwise, within 20 minutes at l3l5C, to a'solution of 42.77 g of thiophosgene in 400 ml of dioxane. The mixture is stirred at room temperature for 10 hours. It is then l served. The solut10n. is further stlrred overmght, and l lllto gf z and PH 1 li wlt h then stirred into 1.5 liters of ice water. Neutralisation is :3 1d z i to p i e prelglpltate .performed in the cold state with 2N NaOl-l, and the tired 0 ed ri l- 8:515? crystalline precipitate chromatographed with methy- P P i t elresu exy lene chloride through silica gel. The pure final product 15 .EFS' fH F Q g me 5 3 I melts at 5860C and has the following structure: 1 e o owmg ,lsot locyanopyn mes 0 Ormufa a can be prepared in the same manner as that descr bed in Example 1: SCN OCH SCN EXAMPLE 4 1R1 (Ia) Preparation of 2-n-hexylam1no-5-1soth1ocyanopyr1d1ne 25 A (Compound No. 58) H 2 SCN- Physical Comp. No. position R, R1 characteristics 1 5 H CH m 6365C 2 5 H CH CH n 1,670 3 3 6C! CH,CH 4 5 H n-C H, 1,666 5 5 H iso-C H n 1,6694 6 5 H n-C,H, 11,," 1,6548 7 5 H se :.C l-l n 1,670 8 5 H C(CH mp. 7072C 9 5 H n-C H 11,, 1,6212 10 5 H C(CH CH =CH 11,, 1,6418 11 5 H CH CH,CH(CH,-,) 1,6371 12 5 H n-C H 1,6215

13 5 H m 58-60C 14 5 H CH(CH,CH )CH,CH,CH-,. n,, 1,6255 15 5 H (:H,CH,C(CH, n,, 1,6168 16 5 H n-C,H n 1,6089 17 5 H CH CH,CH C(CH 11,, 1,6279 I8 5 H n-C,,H,, 11,, 1,6000 19 5 H n-C H 11,, 1,5883 20 5 H n-C H m 42-44C 21 5 H n-C H 22 5 H n-C H 23 S H CH1CHN(C2H5)2 24 5 H cH -cH -cH -oc H a. 101 g of triethylamine andsubsequently g of The following isothiocyanopyridines of formula lb can n-hexylamino are placed into 600 ml of distilled anhybe prepared in'the same manner as that described in drous ethanol. An amount of 79 g of 2-chloro-5- Example 2: nitropyridine is added portionwise at room tempera- SCN ture in the course of 15 minutes. The mixture is then heated to reflux temperature, whereby it goes into R (1b) solution at C. The solution is stirred for -24 hoursat R the reflux temperature and afterwards cooled to room temperature; the solution is poured into ice/water, and 60 the formed precipitate filtered off. The 2-n-hex- I ylamino-S-nitro-pyridine obtained after 'recrystallisa- Cmnp' i R1 R1 ggg gi tion from ethanol/water melts at 56 57C. 25 5 H H b. 99 g of 2-n-hexylammo-S-mtropyndme 1s d1ssolved 26 5 H 8 10841111; in 1000 ml of distilled ethanol and, after addition of 10 g; g g EQa g of Raney nickel, hydrogenated at room temperature 29 5 H :Id g; to 40C. With 13% and hydrogen absorption, 30 5 H n-c H mp. 88-90"C there are additionally added 10 g and 5 g, respectively, 5 H

The following isothiocyanopyridines of formula lc can In the same manner as that described in Example 4 are be prepared in the same manner as that described in prepared the following isothiocyanopyridines of forformula 3: mula Id, from which corresponding acid addition salts are obtainable:

-continued Comp. No. SCN- R, NR R Physical position characteristics 86 5 H NH Cyclopropyl 87 5 H NH Allyl 88 5 H NCH, CH CH CN 90 5 H NH CH,CH2-OCH3 93 5 H NH CH,-CH N(Cl-l 97 5 H NH CH,(CH ),-N(CH 102 5 H NH (ca) .0

103 5 H NH O- g 104 3 H NH CH,

105 3 H NH C H I06 3 H NH u n I07 3 ,H NCH CH3 v110v H -1 l U H3 3 H N(C,H,,) C,H5

EXAMPLE 5 uct melts at 92 935C and has the following struc- Preparation of 2(4-tert.butylphenylthio )'5-isothiocyanopyridine (Compound No. 1.9).

25.8 g of crude 2-(4-tert.-butylphenylthio)-5- aminopyridine, obtained by catalytic hydrogenation, is dissolved in 200 ml of dioxane. This solution is added dropwise at room temperature, in the course of 10 minutes, to a mixture of 12.5 g of thiophosgene in 200 ml of dioxane, the temperature rising to C. The solution is stirred overnight and subsequently stirred into 1 liter of ice water. The solution is neutralised with 2N NaOH. The crystalline precipitate is purified by means of column-chromatography through silica gel, with methylene chloride as the 'eluant. The pure prodture:

SCN S C(CH EXAMPLE 6 Preparation of Z-benzylthio-Sisothiocyano-pyridine (Compound No. 1.19)

a. 91.4 g of 2-benzylthio-5nitropyridine is dissolved 19 Raney nickel is filtered off under nitrogen by suction; the solvent is then evaporated off under vacuo to obthen slowly added dropwise. The mixture is heated to tain 2-benzylthio-5-amino-pyridine, which is used direct for the subsequent thiophosgenisation.

b. 76.7 g of 2-benzylthio-5-amino-pyridine in 200 ml of dioxane is added dropwise at 35C, in the course of 20 minutes, to a solution of 46.2 g of thiophosgene in 300 ml of dioxane; stirring is subsequently continued for 12 hours at room temperature. The solution is then stirred into 1 liter of ice water, and the formed precipitate filtered off under suction. After purification by chromatography with methylene chloride through silica gel, the final product melts at 58-60C.

EXAMPLE 7 Preparation of 2-(4-chlorophenylsulphonyl)-5-isothiocyano-pyridine (Compound No. 2.3)

a. 53.5 g of 2-(4'-chlorophenylthio-5-nitro-pyridine is added portionwise at room temperature to a solution of 500 ml of glacial acetic acid, 48 ml of H O (33%), and 4 ml of conc. H SO After 24 hours, the solution is stirred into 2 liters of ice water: the resulting precipitate is filtered off under suction, and chromatographed through silica gel. The product then has a melting point of l87l89C and is pure.

b. 24.5 g of 2-(4-chlorophenylsulphonyl)-5- nitropyridine is dissolved in 300 ml of ethanol, and the solution, after the addition of 3 g of Raney nickel, hydrogenated at a temperature of between 20 and C until the reaction ceases. Raney nickel is filtered of under nitrogen by suction. The solvent is evaporated off under vacuo to obtain 2-(4'-chlorophenylsulphonyl)-5-amino-pyridine, which is further processed in the crude state.

c. A solution of 14 g of 2-(4-chlorophenylsulphonyl)-5-amino-pyridine is added dropwise at room temperature, in the course of 10 minutes, to a solution of 6.6 g of thiophosgene in 100 ml of dioxane, and

stirring is then continued for 12 hours at the, same (scm gjjg R temperature. The solution is then stirred into 500 ml of ice water; filtration under suction is performed and purification by chromatography with methylene chloride through silica gel; M.P. of product 163-l65C.

EXAMPLE 8 Preparation of 2-phenoxy-5-isothio-cyanopyridine (Comp. 3.1)

EXAMPLE 9 Preparation of 2-(4f-methoxyanilino)-5-isothiocyano-pyridine (Compound No. 4.40)

a. 24.62 g of p-anisidine is placed into 300 ml of distilled anhydrous ethanol, and 20.2 g of triethylamine 60C and, at this temperature, 31.7 g of 2-chloro-5- nitropyridine stirred in portionwise. Stirring is subsequentlymaintained during 90 minutes at reflux temperature. The solution is cooled to room temperature and poured into ice water; the precipitate is then filtered off and washed well with water. After recrystallisation from ethanol/water, the .,resulting .2-(4'-methoxyanilino)5-nitropyridine melts at l55l57C.

b. 62.4 g of 2-(4-methoxyanilino)-5-nitropyridine is dissolved in 550 ml of distilled ethanoland, after the addition of Sig of Raney nickel, the solution hydrogenated' at room temperature to 35C. With 33% hydrogen absorption, a further 6 g of Raney nickel is added. The Raney nickel catalyst is filtered off with suction, and the ethanol completely removed from the filtrate. The resultant 2-(4-methoxyanilino)-5-aminopyridine is sufficiently pure for the next step.

c. 50 g of 2-(4'-methoxyanilino)-5-aminopyridine in 300 ml of distilled anhydrous dioxane is added dropwise at 15C, within 15 minutes, to a solution of 26.8 g of thiophosgene in 200 ml of dioxane. The mixture is subsequently stirred at room temperature for 15 hours; it is then poured into ice/water, and the mixture adjusted to pH 8 with solid sodium bicarbonate. The precipitate is filtered off and washed neutral with water. The solid substance is dissolved in methylene chloride, and the organic phase washed with water and dried with magnesium sulphate. The solution is concentrated in a rotary evaporator, and the resulting product purified by column-chromatography through silica gel, with methylene chloride as the eluant.

The thus obtained melts at 137139C.

The following isothiocyanopyridines of formula Ia can be prepared in "the same manner as that described in Examples 5 and 6:

2-( 4 -methoxyanilino )-5 -isothiocyanopyridine Com Compound Physical data 1.1 2-Phenylthio-5-isothiocyano- M.P. 52-54C pyridine 1.2 6-PhenylthiO-S-isothiocyano- M.P. 8284C pyridine 1.3 4-(4-Isothiocyanophenylthio)- M.P. 72C

pyridine 1.4 2-(4-Methylpheny1thio)-5-iso- M.P. 63-67C 1 thiocyano-pyridine 1.5 2-(3'-Methylphenylthio)'5-iso- M.P. m," 1,668 thiocyano-pyridine 1.6 2'-(4-Methylphenylthio)-3-iso- M.P. 66-67C thiocyano-py'ridine 1.7 2-(2-Isopropy1phenylthio)5 M.P. 38-'40.C-

isothiocyanmpyridine I v 1.8 2-(2'-Isopropylphnylthio) 3- M.P. 6062C I is'othiocyano-pyridine I i 1.9 2-(4'-tert., Butylphenylthio)-5- M.P..92-931, 5C

isothiocyano-pyridine l. 10 2-(41-Fluorophenylthio)-5 isothiocyano-pyridine 1.1 l :2-(4 -Chloropheny1thio)-5-iso M.P. 6061, 5C thiocyano-pyridine 1.12 2-(4-Chloropheny1thio)-3 isothio- M.P. 5960C cyano-pyridine -continued Comp. Com Compound Physical data Compound Phys'cal data 4.16 2-(4"-Methoxy;lcarbonylamino- 7 My. 57 586C an|l1 no)--1s0t locyano-py ndme i1no 2 2{i1011,' s -1 P pyridine an111no)-5-1s0th1ocyano-pyr1d1ne 3.25 2-(2',6k;Dichl ;ro-4:js0thi0- i31%.;33339553311?" cyanop enoxy -pyr1 me 6 3.26 Z-(3',4',5'-TriChl%r0phen0Xy)-5- M.P.127129C ifi gi ffii iiii'fie My. 132 C isothiocyano-pyri ine 6 3.27 2-BSinzyloXy-5-is0thi0cyan0- M.P. 7678C 10 82 85 C pyn 1H6 3.28 2-(4'-lsothiocyanobenzyloxy)- M.P. 110112C gg g ggfifi fggg pyridine 3.29 2-(4'-FiLlOr0benZyl0Xy)'5-iS0[hiO- M.P. 118-120C i g ggf fi gg cyano-pyridine 3.30 2-4'-Fluoroben;yl0xy)-31so- 4' gfi g gggf gf m'g ammo] 5 l diilii 4.24 2-[N-(3',4-Dimethylbenzyl)- aggxyazazvgxgt F uoro' amino]-S-isothiocyano-pyridine 3.32 2-g2'-Flu6r6b n y16x )-5456- M.P. 5456C 415 ;g f;fg ?g" mmyawpwdme 4.26 2-(4'-Phenylanilin0)-5-is0thi0- M.P. 175-179 0 I o cyano pyridine figgggggfgfgfifg 5 135 C 4.27 2- (4'-ISOthi0Cyan0anil1n0)-5- M.P. 179181C 3.34 2-(4-Bromobegzyloxy)-5-iso- M.P. 146-148C 4 28 giaffig'ggggzy thiocyano-pyri ine -2-(4};-Methylbenggioxyyi M'P' 95-98%: 4 29 g l il i i o i anoanilin0)-6- lsot 1ocyano-pyr1 lne a 3.36 2-(2' PhenfilethoXfl-S-iSOthlO- M.P. 110-114 c 4 3O 52 g 8 3353 cyano-pyn me a 3.37 2-(3-Phenglpropoxyy5-1soth1o- M.P. 72-76 C 1 4 31 3 2g}:igi gg ggggfi y cyano-pyn me 'troridine 3.38 2-Benzyloxy-5-1soth1ocyano-6- I methomfpyfidine h 6 4.32 2, yfl tidilnseoth1ocyan0an1l1n0) 3.39 2-Benzy oxy-S-isot iocyanodiethylamino pyridine 4.33 ggdilnsgthiocyanoanlhno) 4.34 2-(3 '-Isothiocyanoanilino)- pyridine H In the same manner as that described in Example 9, 'g iagfgkg g gg' there can be prepared the following isothiocyanopyri- 4.36 2-(4-Methylanilino)-5-is0thiodines of the eneral f rmula I d from which corre- Y y-Py g o 4.37 2-[N-(4-Chlorobenzyl)-amino]- spondmg ac1d add1t1on salts are obta1nable. 35 5-isothiocyan0-6meth0Xypyridine R 4.38 2-(4'-Isothiocyanoanilino)-4- R 3 methyl-pyridine 2 5) 4.39 2-(4 '-Methylanilino)-5-isothio- R H n cyano-6-diethylamino-pyridine l 4.40 2-(4'-Methoxyanilin0)-5-isothio- M.P. l37l39C (CH 6 q \R 40 cyano-pyndine (scN) TESTS ON MICE INFESTED BY HYMENOLEPIS (I d) NANA The active substances 1n the form of a suspens1on g?- Com ound Ph Sical data were administered by stomach probe to white mice p y infested with Hymenolepis nana. Five animals were gIafl fgfiigsgwaggggg 123:} 5% used for each test. The active substances were adminiscyano pyridine tered to each animal once daily on three successive 4.3 2-(4'-ChlogqanilinQ-S-isothio- M.P. 118-12lC days. On the eighth day after commencement of the cyano-pyn me H4I Bromoanilino) 5 isothio M.P. 110 113oC treatment, the ammals were killed and dlssected.

cyano-pyridine After dissectlon of the test animals, an evaluatlon was igg ggg g gzg made on the basis of the number of tapeworms present 4.6 2-(4-Methylanilino)-5-isothio- M.P. 136-138C in the intestines. Untreated mice which had been simul- 4 7 gyg zpi sqg T s taneously and identically infested served as a control. I 111i6c a6J i 0- The agents were tolerated asymtomatically by the 4.8 2-(3 ,4 -Dichloroanilino)-5-is0- mlce thiocyano-pyridine -(fg qh TESTS ON MICE INFESTED BY MOUSE 1s0 locyano-pyn 1ne 4.10 2-(3 -Trifluoromethylanilino)-5 THREADWORMS (OXYURIS) isothiocyano-pyridine H H4, EthoxyanmnO) 5 iSothio MP. 1366C The act1ve substances were admlmstered 1n the form cyano-pyridine of a suspension by means of a stomach probe to wh1te :2' MR 104-107 C mice infested with mouse threadworms. Five animals 1 4 ]3 92 gx 65 were used for each test. The active substances were cyano-pyridine o admmlstered to each animal once daily during three fi' gg 'gggfgj ggglg Hm] C successive days. The animals were then killed on the 5 2 (4uDimethylaminoanilino) 5 M p 149 150-C eighth day after commencement of the treatment and isothiocvano-Dvn'dine dissected.

.. :25 After dissection of the test animals, an evaluation was made on the basis of the count of mouse threadworms present in the intestines. Untreated mice that had been identically infested served as a control.

The agents were tolerated asymtomatically by the mice.

TESTS ON MICE INFESTED BY NEMATOSPIROIDES DUBIUS The active substances in, the form of a suspension were administered by stomach probe to white mice infested with Nematospiroidesdubius. Five animals were used for each test. The active substances were administered to each animal once daily on three successive days. On the eighth day after commencement of the treatment, the animals were killed and dissected.

After dissection of the test animals, an evaluation was made on thebasis of the. count of nematodes present in the intestines. Untreated mice whichhad been simultaneously and identically infested served as a control.

The agents were tolerated asymtomatically by the mice.

DETERMINATION OFITI-IE ANTHELMINTIC ACTION OF FOWL INFESTED WITH ASCARIDIA GALLI' H Oneto three-day old chickens were infested with eggs of Ascaridia galli (asc'arides). A group of five chickens was used for each'testj Four to five weeks TESTS ON RATS INFESTED BY FASCIOLA HEPATICA White laboratory rats were infested with common liver flukes (Fasciola hepatica). After expiration of the prepatent period, the infestation of the rats by common liver flukes was determined by means of three independent excrement analyses.

In each test, two infested rats were treated in each case with the active substance, administered in the form of a suspension by stomach probe, once daily on three successive days. An excrement analysis to determine the content of common liver fluke eggs was made once weekly in the third, fourth and fifth week after administration of the active substance. At the end of the fifth week after commencement of the test, the test animals were killed and examined to determine whether liver flukes were still present.

The effectiveness of the isothiocyanopyridines according to the invention as defoliating and desiccating agents is illustrated by the following tests.

The active substances are applied, either (a) as a 0.5% aqueous suspension (obtained from a 25% emulsion concentrate) or (b) as a powder concentrate, to ca. cm high cotton plants, shortly before the appearance of the third leaf. In each case, it is only the surface and the stem of the leaf of the cotyledons which are treated. The plants are then stored in a greenhouse COATED GRANULATE Composition: 25.0 parts of an active compound of formula I, 450 parts of microcrystalline cellulose, 2.5 parts of highly dispersed silicic acid, 7.5 parts of talcum, and 20.0 parts of polyvinyl acetate.

The active substance, talcum and ca. 90% of the amount of silicic acid are successively worked into the solution of polyvinyl acetate in acetone/ethyl acetate mixture (1:1), and the whole mixed with the prepared portion of microcrystalline cellulose in a planetary mixer. The remainder of the silicic acid is subsequently added to the mixture, and this then kneaded until ready for granulation. The mixture is transferred to an oscillator-granulator and granulated to the desired particle size. The resulting granulate is dried and again granulated in a granulator down to a particle size of 30-300 IL.

DISPERSIBLE POWDER The following constituents are used in the tion of 50% dispersible powders:

50 parts of an active substance according to the inventron,

1 part of a polyethyleneoxypropylene glycol having a molecular weight of ca. 2000 (Pluronic L 61),

5 parts of the ammonium salt of a sulphonated naphthalene sulphonic acid/phenol/formaldehyde condensate (Irgatan AGl 44 parts of kaolin;

50 parts of an active substance according to the invention,

1 part of a polyethyleneoxypropylene glycol having a molecular weight of ca. 8000 (Pluronic F 68),

0.5 part of sodium lignin sulphonate,

48.5 parts of sodium silicate.

The active substances are mixed with the carriers and distributing agents and finely ground. The resulting powder can be mixed with liquid or pasty feeding stuffs and thus administered to domestic and farm animals.

PASTE The following substances are used in the preparation of a 40% paste: 40.0 parts of an active substance according to the invention, 2.5 parts of sodium lignin sulphonate, 0.3 part of sodium benzoate, 10.0 parts of polyoxyethylenealkyl ether,

prepara- 47.2 parts of distilled water.

FEED ADDITIVE PRESS CAKES The following substances are used in the preparation of 35% feed additive press cakes:

35 parts of an active substance according to the invention,

parts of molasses,

5 parts of licorice powder,

parts of dried green meal,

20 parts of ground bran.

The active substance and the distributing agents are mixed and formed into press cakes in an animal-feedpress. The feed additive concentrate obtained is mixed with the feed and thus administered to domestic and farm animals.

EMULSIFIABLE CONCENTRATE An emulsifiable concentrate is obtained by mixing together the following substances:

2 parts of an active substance according to the invention, 7 2 parts of a polyethyleneoxypropylene glycol having a molecular weight of ca. 3000 (Pluronic L 64), and 96 parts of acetone.

The concentrate obtained can be diluted with water to give emulsions of any desired concentration, and administered, e.g., as drink, to domestic and farm animals.'

OILY FORMULATION 40 parts of active substance according to the invention are ground as finely as possible in a suitable mill,-and then homogeneously mixed, e.g., on a roll mill, with 60 parts of arachis oil (peanut oil).

These oily pastes can be administered orally to the animals.

We claim: 1. A compound of the formula 

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 in which the -NCS group is in the 5- position.
 3. The compound of claim 2 which is 2-n-hexylmercapto-5-isothiocyanopyridine.
 4. The compound of claim 2 which is 2-n-heptylmercapto-5-isothiocyanopyridine. 